This invention is directed to novel compounds possessing angiotensin converting enzyme (ACE) inhibitory activity and/or neutral endopeptidase (NEP) inhibitory activity and methods of preparing such compounds. This invention is also directed to pharmaceutical compositions containing such ACE and/or NEP inhibiting compounds or pharmaceutically acceptable salts thereof and the method of using such compositions.
The compounds of this invention are those of the formula (I) 
including a pharmaceutically acceptable salt thereof where:
x is 0 or 1;
R is H, alkyl, alkenyl, aryl-(CH2)pxe2x80x94, heteroaryl-(CH2)pxe2x80x94, cycloheteroalkyl-(CH2)pxe2x80x94, or
R can be joined together with the carbon to which it is attached to form a 3 to 7 membered ring which may optionally be fused to a benzene ring;
R1 is H or xe2x80x94COR2 where R2 is alkyl, aryl-(CH2)pxe2x80x94, cycloheteroalkyl-(CH2)pxe2x80x94, heteroaryl-(CH2)pxe2x80x94, alkoxy, or cycloalkyl-(CH2)pxe2x80x94;
p is O or an integer from 1 to 8; and
A is a dipeptide derived from one or two non-proteinogenic amino acid or is a conformationally restricted dipeptide mimic as described below.
A is a dipeptide derivative of the structure 
where R1a, R1b, R2a and R2b are independently selected from H, alkyl, aryl-(CH2)pxe2x80x94, cycloalkyl, cycloheteroalkyl-(CH2)pxe2x80x94, heteroaryl-(CH2)pxe2x80x94, biphenylmethyl, or
R1a and R1b or R2a and R2b may be joined together to the carbon to which they are attached to form a 3 to 7 membered ring, optionally fused to a benzene ring; and 
xe2x80x83refers to an optional 5 or 6 membered ring containing a single hetero atom and which may optionally include an R5 substituent (as shown) which is H, alkyl, aryl-(CH2)p or cycloalkyl-(CH2)p, cycloheteroalkyl-(CH2)p, or cycloheteroaryl-(CH2)pxe2x80x94;
R3 is H, alkyl or aryl-(CH2)pxe2x80x94;
R4 is OH, Oalkyl, Oxe2x80x94(CH2)paryl- or NR1(R2) where R1 and R2 are independently H, alkyl, or aryl(CH2)p or heteroaryl-(CH2)pxe2x80x94;
with the proviso that in A(1) at least one of 
xe2x80x83is other than a natural xcex1-amino acid, and thus must be other than valine, leucine, phenylalanine, tyrosine, serine, cysteine, threonine, methionine, aspartic acid, glutamic acid, arginine, lysine or proline.
In addition, A can be a conformationally restricted dipeptide mimic which has the structure 
and is a non-proteinogenic dipeptide.
Thus, the compound of formula I include 
The term xe2x80x9cconformationally restricted dipeptide mimicxe2x80x9d refers to a structural skeleton which has the attributes of a conventional dipeptide 
but having enhanced biological properties due to additional bonds which limit the rotational freedom.
Examples of the A(2) dipeptide mimics include any of the conformationally restricted dipeptide mimics set out below. 
With respect to A(5), R11 and R12 are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl-(CH2)mxe2x80x94, aryl-(CH2)mxe2x80x94, substituted aryl-(CH2)mxe2x80x94, and heteroaryl-(CH2)mxe2x80x94, or R11 and R12 taken together with the carbon to which they are attached complete a saturated cycloalkyl ring of 3 to 7 carbons, or R11 and R12 taken together with the carbon to which they are attached complete a keto substituent, i.e., 
with respect to A(13) R8, R9 and R7 are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl-(CH2)mxe2x80x94, aryl-(CH2)mxe2x80x94, substituted aryl-(CH2)mxe2x80x94, and heteroaryl-(CH2)mxe2x80x94;
R10 and R6 are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl-(CH2)mxe2x80x94, aryl-(CH2)m, substituted aryl-(CH2)mxe2x80x94, and heteroaryl-(CH2)mxe2x80x94, or R6 and R10 taken together with the carbon to which they are attached complete a saturated cycloalkyl ring of 3 to 7 carbons, R6 and R8 taken together with the carbon to which they are attached complete a saturated cycloalkyl ring of 3 to 7 carbons, or R9 and R10 taken together with the carbon to which they are attached complete a saturated cycloalkyl ring of 3 to 7 carbons;
m is zero or an integer from 1 to 6;
R4 is OH, Oalkyl, Oxe2x80x94(CH2)m-heteroaryl, 
xe2x80x83Oxe2x80x94(CH2)m-aryl, or 
xe2x80x83or NR1(R2);
where R1 and R2 are independently H, alkyl, aryl(CH2)p, aryl or heteroaryl;
R14 is hydrogen, lower alkyl, cycloalkyl, or phenyl;
R15 is hydrogen, lower alkyl, lower alkoxy or phenyl;
R16 is alkyl or aryl-(CH2)mxe2x80x94; and
R17 is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl-(CH2)mxe2x80x94, aryl-(CH2)mxe2x80x94, substituted aryl-(CH2)mxe2x80x94, or heteroaryl-(CH2)mxe2x80x94.
R18 is H, alkyl or alkenyl, and R18 and R17 may be taken together with the carbon and nitrogen to which they are attached to complete a saturated N-containing ring of 5 or 6 ring members.
R19 is H or an alkyl, and in A(4), R19 and x (which is CH2) together with the carbons to which they are attached may form an aromatic ring of carbons (as in A(15).
The starting compounds H-A(1) and H-A(2) are described in the literature or are obtained by modifications of known procedures. For example, the starting compounds of formula H-A(1) or H-A(2) wherein A(1) or A(2) is as defined in formulas A(5), A(13), A(16), A(21), where Y (where present) is CH2 are disclosed by Thorsett et al., J. Med. Chem., 29, p. 251-260 (1988), Harris et al. in U.S. Pat. Nos. 4,587,050, 4,587,238, 4,629,787 and Yanagisawa et al. in U.S. Pat. No. 4,734,410.
The starting compounds of formula H-A(1) or H-A(2) wherein A(1) or A(2) is as defined in formulas A(3) and A(13) where Y is S(O)n are disclosed by Yanagisawa et al., J., Med. Chem., 30, p. 1984-1991 (1987) and 31, p. 422-428 (1988), Karanewsky in U.S. Pat. No. 4,460,579, Cheung et al. in U.S. Pat. No. 4,594,341, and Yanagisawa et al. in U.S. Pat. No. 4,699,905.
The starting compounds of formula H-A(1) or H-A(2) wherein A(1) or A(2) is as defined in formula A(5) are disclosed by Karanewsky in U.S. Pat. Nos. 4,460,579 and 4,711,884.
The starting compounds of formula H-A(1) or H-A(2) wherein A(1) or A(2) is as defined in formulas A(3) (Y is xe2x80x94CH2xe2x80x94, and A(21) are disclosed by Watthey et al., J. Med. Chem., 28, p. 1511-1516 (1985) and Watthey in U.S. Pat. Nos. 4,410,520, 4,470,988, 4,473,575, 4,537,885 and 4,575,503 and also by Parsons et al., Biochemical and Biophysical Research Comm., 117, p. 108-113 (1983) and in U.S. Pat. No. 4,873,235.
The starting compounds of formula H-A(1) or H-A(2) wherein A(1) or A(2) is as defined in formula A(3) and Y is S or O are disclosed by Slade et al., J. Med. Chem., 28, p. 1517-1521 (1985) and in U.S. Pat. No. 4,477,464 and Itoh et al., Chem. Pharm. Bull., 34, p. 1128-1147 (1986) and 34, p. 2078-2089 (1986) as well as Sugihara et al. in U.S. Pat. No. 4,548,932 (Y is O) and Katakami et al. in U.S. Pat. No. 4,539,150 (Y is S).
The starting compounds of formula H-A(1) or H-A(2) wherein A(1) or A(2) is as defined in formula A(16) can be prepared by reduction of the corresponding starting compounds wherein A(1) or A(2) is as defined in formula A(3).
The starting compounds of formula H-A(1) or H-A(2) wherein A(1) or A(2) is as defined in formula A(22) are disclosed by Flynn et al in U.S. Pat. No. 4,973,585.
The starting compounds of formula H-A(1) or H-A(2) wherein A(1) or A(2) is as defined in formula A(10) and Y is S, xe2x80x94SO, or xe2x80x94SO2 are disclosed by Harris et al. and Patchett et al. in U.S. Pat. Nos. 4,415,496 and 4,617,301.
The starting compounds of formula H-A(1) or H-A(2) wherein A(1) or A(2) is as defined in formula A(10) and Y is CH2, and is as defined in formula A(23) where X2 is CH2 is disclosed by Thorsett, Actual. Chim. Ther., 13, p. 257-268 (1986).
The starting compounds of formula H-A(1) or H-A(2) wherein A(1) or A(2) is as defined in formulas A(11) and A(19) and A(20) are disclosed by Attwood et al., Federation of European Biochemical Studies, 165, p. 201-206 (1984) and in U.S. Pat. No. 4,512,994 and Natoff et al., Drugs Of The Future, 12, p. 475-483 (1987).
The starting compounds of formula H-A(1) or H-A(2) wherein A(1) or A(2) is as defined in formula A(12) are disclosed by Huang et al. in U.S. Pat. No. 4,465,679.
The starting compounds of formula H-A(1) or H-A(2) wherein A(1) or A(2) is as defined in formula A(18) are disclosed by Bolos et al. in Tetrahedron, 48, p. 9567-9576 (1992).
The starting compounds of formula H-A(1) or H-A(2) wherein A(1) or A(2) is as defined in formulas A(4) and A(15) are disclosed in European Patent Application 0629627A2.
The starting compounds of formula H-A(1) or H-A(2) wherein A(1) or A(2) is as defined in formula A(9) are disclosed in U.S. application Ser. No. 100,408 (file HA611).
The starting compounds of formula H-A(1) or H-A(2) wherein A(1) or A(2) is as defined in formulas A(7) and A(8) are disclosed in European Patent Application 481,522 (Flynn et al) and European Patent Application 0534363A2 (Warshawsky et al).
The starting compounds of formula H-A(1) or H-A(2) wherein A(1) or A(2) is as defined in formula A(14) are disclosed in U.S. application Ser. No. 153,854 (file HA615).
The starting compounds of formula H-A(1) or H-A(2) wherein A(1) or A(2) is as defined in formula A(17) are disclosed in European Patent Application 0599444A1 (Barrish et al).
In addition, in accordance with the present invention, a pharmaceutical composition is provided which includes a therapeutically effective amount of compound I and a pharmaceutically acceptable carrier therefor.
The pharmaceutical composition as defined above will be useful in the treatment of cardiovascular diseases such as hypertension and/or congestive heart failure.
Furthermore, in accordance with the present invention, a method is provided for treating a cardiovascular disease such as hypertension and/or congestive heart failure, as well as other diseases as set out hereinafter, which includes the step of administering to a mammalian species, including humans, dogs and cats, a therapeutically effective amount of a composition as defined above.